Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19+ hematological malignancies, including durable ...complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells. Alternatively, T cells from a healthy donor can be used to produce an allogeneic CAR T therapy, provided the cells are rendered incapable of eliciting graft versus host disease (GvHD). One approach to the production of these cells is gene editing to eliminate expression of the endogenous T cell receptor (TCR). Here we report a streamlined strategy for generating allogeneic CAR T cells by targeting the insertion of a CAR transgene directly into the native TCR locus using an engineered homing endonuclease and an AAV donor template. We demonstrate that anti-CD19 CAR T cells produced in this manner do not express the endogenous TCR, exhibit potent effector functions in vitro, and mediate clearance of CD19+ tumors in an in vivo mouse model.
MacLeod and colleagues use a homing endonuclease and an AAV vector to insert an anti-CD19 CAR into the TRAC gene to create universal allogeneic CAR T cells. Targeted insertion of a CAR transgene may allow the generation of more homogeneous CAR T cell products with more predictable safety and efficacy profiles.
Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor ...microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice.
Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment.
This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment.
Women can develop posttraumatic stress disorder in response to experienced or perceived traumatic, often medically complicated, childbirth; the prevalence of these events remains high in the United ...States. Currently, no recommended treatment exists in routine care to prevent or mitigate maternal childbirth-related posttraumatic stress disorder. We conducted a systematic review and meta-analysis of clinical trials that evaluated any therapy to prevent or treat childbirth-related posttraumatic stress disorder.
PsycInfo, PsycArticles, PubMed (MEDLINE), ClinicalTrials.gov, CINAHL, ProQuest, Sociological Abstracts, Google Scholar, Embase, Web of Science, ScienceDirect, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for eligible trials published through September 2023.
Trials were included if they were interventional, if they evaluated any therapy for childbirth-related posttraumatic stress disorder for the indication of symptoms or before posttraumatic stress disorder onset, and if they were written in English.
Independent coders extracted the sample characteristics and intervention information of the eligible studies and evaluated the trials using the Downs and Black’s quality checklist and Cochrane’s method for risk of bias evaluation. Meta-analysis was conducted to evaluate pooled effect sizes of secondary and tertiary prevention trials.
A total of 41 studies (32 randomized controlled trials, 9 nonrandomized trials) were reviewed. They evaluated brief psychological therapies including debriefing, trauma-focused therapies (including cognitive behavioral therapy and expressive writing), memory consolidation and reconsolidation blockage, mother-infant–focused therapies, and educational interventions. The trials targeted secondary preventions aimed at buffering childbirth-related posttraumatic stress disorder usually after traumatic childbirth (n=24), tertiary preventions among women with probable childbirth-related posttraumatic stress disorder (n=14), and primary prevention during pregnancy (n=3).
A meta-analysis of the combined randomized secondary preventions showed moderate effects in reducing childbirth-related posttraumatic stress disorder symptoms when compared with usual treatment (standardized mean difference, −0.67; 95% confidence interval, −0.92 to −0.42). Single-session therapy within 96 hours of birth was helpful (standardized mean difference, −0.55). Brief, structured, trauma-focused therapies and semi-structured, midwife-led, dialogue-based psychological counseling showed the largest effects (standardized mean difference, −0.95 and −0.91, respectively). Other treatment approaches (eg, the Tetris game, mindfulness, mother-infant–focused treatment) warrant more research. Tertiary preventions produced smaller effects than secondary prevention but are potentially clinically meaningful (standardized mean difference, −0.37; −0.60 to −0.14). Antepartum educational approaches may help, but insufficient empirical evidence exists.
Brief trauma-focused and non–trauma-focused psychological therapies delivered early in the period following traumatic childbirth offer a critical and feasible opportunity to buffer the symptoms of childbirth-related posttraumatic stress disorder. Future research that integrates diagnostic and biological measures can inform treatment use and the mechanisms at work.
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While RNA-pulsed dendritic cell (DC) vaccines have shown promise, the advancement of cellular therapeutics is fraught with developmental challenges. To circumvent the challenges of cellular ...immunotherapeutics, we developed clinically translatable nanoliposomes that can be combined with tumor-derived RNA to generate personalized tumor RNA-nanoparticles (NPs) with considerable scale-up capacity. RNA-NPs bypass MHC restriction, are amenable to central distribution, and can provide near immediate immune induction.
We screened commercially available nanoliposomal preparations and identified the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as an efficient mRNA courier to antigen-presenting cells (APCs). When administered intravenously, RNA-NPs mediate systemic activation of APCs in reticuloendothelial organs such as the spleen, liver, and bone marrow. RNA-NPs increase percent expression of MHC class I/II, B7 co-stimulatory molecules, and maturation markers on APCs (all vital for T-cell activation). RNA-NPs also increase activation markers on tumor APCs and elicit potent expansion of antigen-specific T-cells superior to peptide vaccines formulated in complete Freund's adjuvant. We demonstrate that both model antigen-encoding and physiologically-relevant tumor-derived RNA-NPs expand potent antitumor T-cell immunity. RNA-NPs were shown to induce antitumor efficacy in a vaccine model and functioned as a suitable alternative to DCs in a stringent cellular immunotherapy model for a radiation/temozolomide resistant invasive murine high-grade glioma.
Although cancer vaccines have suffered from weak immunogenicity, we have advanced a RNA-NP formulation that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy. RNA-NPs can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity.
Background
Tinea pedis is often chronic or recurrent, but not all individuals are equally susceptible to this infection. Dermatophytes are able to induce the expression of antimicrobial peptides and ...proteins (AMPs) in human keratinocytes and certain AMPs can inhibit the growth of dermatophytes.
Objective
The focus of this study was to analyse the secretion of relevant AMPs, especially RNase 7, human beta‐defensin‐2 (hBD‐2) and the S‐100 protein psoriasin (S100A7), in patients with confirmed tinea pedis.
Methods
To verify the diagnosis, skin scales were obtained from all patients (n = 13) and the dermatophytes were identified by potassium hydroxide mount, culture and molecular analysis. To determine the AMP concentrations, the lesional skin area of the foot was rinsed with a buffer that was subsequently analysed by ELISA. The corresponding area of the other unaffected foot as well as defined healthy skin areas of the forearm and forehead and samples from age and gender‐matched healthy volunteers served as controls.
Results
In tinea pedis patients the AMP concentrations were higher in lesional skin than in non‐lesional skin and in healthy skin of controls. In particular, concentrations of hBD‐2 and psoriasin were significantly elevated.
Conclusions
The induction of AMPs in tinea pedis might be triggered directly by the dermatophytes; furthermore, attendant inflammation and/or differentiation processes may play a role. Our results indicate that there is no defect in the constitutive expression and induction of the analysed AMPs by dermatophytes in the epidermis of affected patients. However, it is not known why the elevated AMP concentrations fail to efficiently combat dermatophyte growth.
The use of telemedicine has been described for various medical conditions. Telemedicine can improve access to care, reduce geographic barriers, and optimise healthcare for patients. The role of ...telemedicine has been described in antimicrobial stewardship programmes for the management of both acute and chronic infectious diseases, including HIV and hepatitis. The goal of this review is to provide data on the implementation of synchronous telemedicine programmes to provide infectious disease management.
Medulloblastoma (MB) is the most common pediatric brain tumor with few reports of successful immunologic targeting. We have recently demonstrated the immune tumor microenvironment as well as response ...to immune checkpoint blockade differ across subtypes of murine MB.
While most often transient, brachial plexus birth injury can cause permanent neurologic injury. The major risk factors for brachial plexus birth injury are fetal macrosomia and shoulder dystocia. The ...degree of injury to the brachial plexus should be determined in the neonatal nursery, as those infants with the most severe injury--root avulsion--should be referred early for surgical evaluation so that microsurgical repair of the plexus can occur by 3 months of life. Microsurgical repair options include nerve grafts and nerve transfers. All children with brachial plexus birth injury require ongoing physical and occupational therapy and close follow-up to monitor progress.
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